The present invention relates to novel compounds and methods for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 14-aza analogs of D, E, and F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the outflow of aqueous humor from the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Another type of drug, beta-blockers, have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G.sub.2, which is subsequently converted to prostaglandin H.sub.2. Other naturally occurring prostaglandins are derivatives of prostaglandin H.sub.2. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). A number of the naturally occurring prostaglandins, including prostaglandins of the F series (such as PGF.sub.2.alpha.), the E series (such as PGE.sub.2) and the D series (such as PGD.sub.2) are known to lower IOP after topical ocular instillation, but can cause marked inflammation as evidenced by conjunctival edema or other untoward effects such as conjunctival hyperemia.
All of the natural prostaglandins known to reduce intraocular pressure, including prostaglandins of the F series (such as PGF.sub.2.alpha.), the E series (such as PGE.sub.2) and the D series (such as PGD.sub.2), have a core cyclopentane ring with alpha and omega chains attached at C-8 and C-12 respectively, as indicated in the following structures: ##STR1##
Currently, the relationship between prostaglandin receptor activation and IOP lowering effects is not well understood. Various publications have reported that PGD.sub.2 receptor activation leads to second messenger activation and in particular, to the stimulation of adenylate cyclase and resultant increases in cAMP levels (Thierauch, Prostaglandins and their Receptors: II. Receptor Structure and Signal Transduction, Journal of Hypertension, volume 12, pages 1-5 (1994). Some believe that PGF.sub.2.alpha. receptor activation, on the other hand, leads to increased outflow of aqueous humor. Regardless of the mechanism, both PGD.sub.2 and PGF.sub.2.alpha. (and certain of its analogs) have been shown to lower IOP. See (for PGD.sub.2) Nakajima, Effects of Prostaglandin D.sub.2 and its analogue, BW245C, on Intraocular Pressure in Humans, Graefe's Archive Ophthalmology, volume 229, pages 411-413 (1991); and (for PGF.sub.2.alpha.), Giuffre, The Effects of Prostaglandin F.sub.2.alpha. the Human Eye, Graefe's Archive Ophthalmology, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F.sub.2.alpha. -1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988).
Synthetic analogs of both the PGD.sub.2 and PGF.sub.2.varies. types have been pursued in the art (Graefe's Archive Ophthalmology, volume 229, pages 411-413 (1991)). Although both types of molecules lower IOP, they have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects have included, among others, an initial increase in IOP and conjunctival hyperemia, (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No.11, pages 44-50 (1993)).
The relationship between EP receptor activation and IOP lowering effects is also the subject of some debate. There are currently four recognized subtypes of the EP receptor: EP.sub.1, EP.sub.2, EP.sub.3, and EP.sub.4 (J. Lipid Mediators Cell Signaling, volume 14, pages 83-87 (1996)). It is known in the art that IOP may be lowered by ligands capable of EP.sub.2 receptor activation, such as PGE.sub.2 and certain of its synthetic analogs (Journal of Ocular Pharmacology, volume 4, number 1, pages 13-18 (1988); Journal of Ocular Pharmacology and Therapeutics, volume 11, number 3, pages 447-454 (1995)), or EP.sub.3 receptor activation (Journal of Lipid Mediators, volume 7, pages 545-553 (1993); Investigative Ophthalmology and Visual Science, volume 31, number 12, pages 2560-2567 (1990)). However, some of these molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing, including an initial increase in IOP, photophobia, and eye ache (see for example Journal of Ocular Pharmacology, volume 4, number 1, pages 13-18 (1988)).
A number of synthetic prostaglandins have been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects in varying degrees which greatly limit their clinical utility. Based on the foregoing, a need exists for the development of molecules that may activate key prostaglandin receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
Attempts have been made by Stjernschantz et al. (U.S. Pat. No. 5,422,368), Woodward et al., (U.S. Pat. No. 5,093,329), Chan et al. (WO 92/08465) and Ueno et al. (U.S. Pat. No. 5,151,444) to reduce selectively or to eliminate altogether the side effects while maintaining the IOP-lowering effect. The Stjernschantz et al. publication is of particular interest because it reports that certain prostaglandin analogs, which possess modifications in the omega chain, still exhibit the intraocular pressure lowering activity of the natural prostaglandins and have fewer adverse effects.
Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by natural D, E, and F series prostaglandins and their synthetic analogs while avoiding some or all of the undesirable side effects usually associated with the use of such compounds. An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a novel class of IOP lowering agents with an improved therapeutic profile over the natural prostaglandins and many of their synthetic analogs. A further object of this invention is to provide methods of using the novel compounds in the treatment of glaucoma and ocular hypertension. It has now unexpectedly been discovered that the presently claimed 14-aza analogs of PGD, PGE, and PGF meet this objective. Certain 14-aza prostanoic acids have been reported (see, U.S. Pat. No. 4,239,778). U.S. Pat. No. 5,387,608 discloses certain 14-sulfonamido prostaglandin analogs for the treatment of glaucoma, and U.S. Pat. No. 5,422,368, mentioned above, discloses prostaglandin analogs in which the omega chain, beyond C-14, may be interrupted with 1-2 heteratoms of oxygen, sulfur and/or nitrogen. The novel compounds of the present invention, however, are neither disclosed nor suggested in the foregoing art.